Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas.
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PURPOSE: Our previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen (CEA) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival. Preclinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3, designated TRICOM) results in a significant improvement in antigen-specific T-cell responses and antitumor activity. We describe here the first trial in humans of the CEA-TRICOM vaccines (also including an enhancer agonist epitope within the CEA gene). PATIENTS AND METHODS: Fifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following: replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM, plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with vaccines, or with divided doses of vaccine with GM-CSF. Vaccines were administered every 28 days for six doses and then once every 3 months. Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule. RESULTS: In this phase I study, no significant toxicity was observed. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having prolonged stable disease (> 6 months). Eleven patients had decreasing or stable serum CEA, and one patient had a pathologic complete response. Enhanced CEA-specific T-cell responses were observed in the majority of patients tested. CONCLUSION: We demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses, and they seem to have clinical benefit in some patients with advanced cancer. (+info)
Immunological synapses are versatile structures enabling selective T cell polarization.
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Helper T cells discriminate among different antigen-presenting cells to provide their help in a selective fashion. The molecular mechanisms leading to this exquisite selectivity are still elusive. Here, we demonstrate that immunological synapses are dynamic and adaptable structures allowing T cells to communicate with multiple cells. We show that T cells can form simultaneous immunological synapses with cells presenting different levels of antigenic ligands but eventually polarize toward the strongest stimulus. Remarkably, living T cells form discrete foci of signal transduction of different intensities during the interaction with different antigen-presenting cells and rapidly relocate TCR and Golgi apparatus toward the cell providing the strongest stimulus. Our results illustrate that, although T cell activation requires sustained signaling, T cells are capable of rapid synapse remodeling and swift polarization responses. The combination of sustained signaling with preferential and rapid polarization provides a mechanism for the high sensitivity and selectivity of T cell responses. (+info)
Analyses of recombinant vaccinia and fowlpox vaccine vectors expressing transgenes for two human tumor antigens and three human costimulatory molecules.
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PURPOSE: The poor immunogenicity of tumor antigens and the antigenic heterogeneity of tumors call for vaccine strategies to enhance T-cell responses to multiple antigens. Two antigens expressed noncoordinately on most human carcinomas are carcinoembryonic antigen (CEA) and MUC-1. We report here the construction and characterization of two viral vector vaccines to address these issues. EXPERIMENTAL DESIGN: The two viral vectors analyzed are the replication-competent recombinant vaccinia virus (rV-) and the avipox vector, fowlpox (rF-), which is replication incompetent in mammalian cells. Each vector encodes the transgenes for three human costimulatory molecules (B7-1, ICAM-1, and LFA-3, designated TRICOM) and the CEA and MUC-1 transgenes (which also contain agonist epitopes). The vectors are designated rV-CEA/MUC/TRICOM and rF-CEA/MUC/TRICOM. RESULTS: Each of the vectors is shown to be capable of faithfully expressing all five transgenes in human dendritic cells (DC). DCs infected with either vector are shown to activate both CEA- and MUC-1-specific T-cell lines to the same level as DCs infected with CEA-TRICOM or MUC-1-TRICOM vectors. Thus, no evidence of antigenic competition between CEA and MUC-1 was observed. Human DCs infected with rV-CEA/MUC/TRICOM or rF-CEA/MUC/TRICOM are also shown to be capable of generating both MUC-1- and CEA-specific T-cell lines; these T-cell lines are in turn shown to be capable of lysing targets pulsed with MUC-1 or CEA peptides as well as human tumor cells endogenously expressing MUC-1 and/or CEA. CONCLUSION: These studies provide the rationale for the clinical evaluation of these multigene vectors in patients with a range of carcinomas expressing MUC-1 and/or CEA. (+info)
CD58 expression decreases as nonmalignant B cells mature in bone marrow and is frequently overexpressed in adult and pediatric precursor B-cell acute lymphoblastic leukemia.
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We used flow cytometry to determine the CD58 expression on nonmalignant B cells at different stages of maturation in the bone marrow and compared it with that of blasts in adult and pediatric precursor B-cell acute lymphoblastic leukemia (B-ALL). The mean fluorescence intensity (MFI) of CD58 expression decreased significantly as nonmalignant B cells differentiated in the bone marrow from an early to a mature stage. Few nonneoplastic B cells at a mid or mature stage of development expressed CD58 MFI values comparable to those seen in leukemic cases. Early-stage nonneoplastic B-cell precursors expressed relatively higher CD58 levels, which frequently overlapped with the variable level of CD58 expression observed among leukemic blasts. As a group, however, the malignant precursor B-ALL cells showed significantly higher expression of CD58 than nonmalignant B-cell populations at any maturational stage. These findings support the potential usefulness of CD58 expression in the diagnosis and monitoring of precursor B-ALL, but only when blasts express high levels of CD58. (+info)
Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules.
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PURPOSE: To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen. EXPERIMENTAL DESIGN: In this phase I study, we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen (CEA) and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]. Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2-restricted peptide derived from cytomegalovirus pp65 protein. RESULTS: Fourteen patients (11 with colorectal cancer and 3 with non-small cell lung cancer) were enrolled and 12 completed at least one cycle of immunization. There were no grade 3/4 toxicities directly referable to the immunizations. One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations. Five other patients were stable through at least one cycle of immunization (3 months). Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients (range, 10-541 CEA-specific cells/10(5) peripheral blood mononuclear cells). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy. A second cycle was not associated with higher T-cell frequencies. Cytokine flow cytometry showed CEA-specific immune response among both CD4(+) and CD8(+) T cells in all immune responders. CONCLUSION: This immunization strategy is safe and activates potent CEA-specific immune responses. (+info)
Acquisition of HLA-DR and costimulatory molecules by T cells from allogeneic antigen presenting cells.
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There is accumulating evidence that cell surface molecules may be transferred between cells during an encounter. The aim of these experiments was to determine whether transfer of allogeneic material to T cells could influence human alloresponses. CD4(+) cells were cocultured with M1 cell (human fibroblast) transfectants expressing HLA-DR1, CD80 and CD86 alone or in combination. Up to 95% of the allogeneic T cells became positive for HLA-DR and the appropriate costimulatory molecules after only 4 h of coculture. The phenomenon required cell contact and cell membrane fluidity because transfer was abolished by transwell separation of the M1 cells and the T cells or by pre-treatment of the APC with paraformaldehyde. Flow cytometric sorting of T cells after coculture and subsequent mixed lymphocyte assays demonstrated that the T cells that had acquired both HLA-DR and costimulatory molecules could act as potent antigen presenting cells. Finally, matured human dendritic cells were also shown to transfer these molecules to CD4(+) cells, which could then act as antigen presenting cells for unprimed T cells and for a cell line specific for an HLA-peptide complex acquired from the DCs. Taken together, these data suggest a novel pathway for the amplification of human alloresponses. (+info)
Differential expression of LFA-3, Fas and MHC Class I on Ad5- and Ad12-transformed human cells and their susceptibility to lymphokine-activated killer (LAK) cells.
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Adenovirus (Ad) E1A is a potent oncogene and has been shown to deregulate the expression of a large number of cellular genes leading to cellular transformation. Here we have analysed the expression of several immunomodulatory molecules on the surface of a set of human cell lines transformed with either Ad12 or Ad5. Human cells transformed with Ad12 demonstrated reduced expression of cell surface LFA-3, Fas and MHC class I when compared to Ad5-transformed cells. Furthermore, Ad12-transformed human cell lines demonstrated greater susceptibility to lysis by lymphokine-activated killer (LAK) cells, compared to Ad5-transformed human cell lines. In contrast, previous studies with rodent cells showed that both Ad5- and Ad12-transformed rat cells were susceptible to LAK cells. Thus, transformation of human cells with Ad5 or Ad12 results in differences in the expression of immunomodulatory molecules on the cell surface and differential recognition of these virus-transformed cells by immune effector cells. (+info)
Immunotherapy with T11TS / S-LFA-3 specifically induces apoptosis of brain tumor cells by augmenting intracranial immune status.
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BACKGROUND: Immunopotentiating agents are the best options in cancer therapeutics because they can specifically destroy tumor cells via immunocytes, which are mostly apoptotic in nature. Previously, immunotherapy with T11TS / SLFA-3 in a ethyl-nitrosourea (ENU)-induced animal model (Druckrey rats) of neural neoplasm showed a significant tumor mass destruction by augmenting the cellular immune status. MATERIALS AND METHODS: The modulations of the peripheral as well as neural immune systems after T11TS administration were monitored by assessing the CD4+ and CD8+ lymphocytes, along with the cytotoxic activity of splenic and brain infiltrating lymphocytes (BIL). The rate of apoptosis of the tumor cells, microglial cells (Mg) and BIL were measured by flow cytometry-based propidium iodide analysis and TUNEL assay. RESULTS: Cell cycle phase distribution analysis by propidium iodide -FACS and TUNEL assay revealed that T11TS administration gradually increased the number of apoptotic brain tumor cells and, at the same time, decreased the number of dividing cells. Up-regulation of the CD4+ and CD8+ lymphocytes were observed after T11TS administration in ENU - induced immunosuppressed animals. A gradual increment of cytotoxicity of splenic and BIL was also demonstrated after successive administration of T11TS. CONCLUSION: These data strongly support the specific apoptosis-inducing role of T11TS in experimental brain tumor cells. Apoptosis of BIL and Mg, that occurred to a much lower level, can be explained in terms of changes in the neural immune system before and after T11TS application. (+info)